CN108409630B - Preparation method of 3-hydroxy-2-indolone derivative in aqueous phase - Google Patents
Preparation method of 3-hydroxy-2-indolone derivative in aqueous phase Download PDFInfo
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Abstract
The invention relates to a synthesis method of a 3-hydroxy-2-indolone derivative in an aqueous phase. The method comprises the steps of adding a 3-substituted-2-indolone compound (1a), a compound of a formula 2a, Sodium Dodecyl Sulfate (SDS) and solvent water into a Schlenk reaction bottle, and putting the reaction bottleStirring and reacting under the conditions of certain temperature and air atmosphere, monitoring the reaction process by TLC or GC until the raw materials completely react, and carrying out aftertreatment to obtain a target product 3-hydroxy-2-indolone derivative (I);
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a synthetic method of a 3-hydroxy-2-indolone derivative.
Background
Natural products have diverse chemical functions and properties, and they play an important role in the development of drugs. Among these, indolones have unprecedented structural diversity and biological activity, and thus have attracted a wide and lasting interest to chemists and biologists. As a subclass of the natural products of indolones, the backbone of 3-hydroxy-2-indolones is likewise a very important biological unit. An increasing number of 3-hydroxy-2-indolone structures are found to constitute the core skeleton of many natural products and have a wide range of biological activities.
As the 3-hydroxy-2-indolone compounds and the derivatives thereof are very important organic intermediates, and a plurality of natural compounds contain the skeletons, the 3-hydroxy-2-indolone compounds have good pharmaceutical activity and are widely applied in the aspects of medicine, biology and the like. Therefore, it is important to develop a convenient, environment-friendly and efficient method for synthesizing 3-hydroxy-2-indolone and its derivatives.
The inventor finds that the synthetic routes for synthesizing and preparing the 3-hydroxy-2-indolone compounds in the prior art mainly comprise the following two routes: one is prepared by ring closure reaction, and the other is prepared by addition reaction of isatin. In recent years, researchers have developed methods for preparing 3-hydroxy-2-indolone compounds from 3-substituted-2-indolone compounds. For example, see the following documents:
(1)“A Dinuclear Palladium Catalyst for r-Hydroxylation of Carbonyls with O2”，Tobias Ritter et.al.，J.Am.Chem.Soc.2011，133，1760-1762；
(2)“A catalytic，mild and efficient protocol for the C-3aerial hydroxylation of oxindoles”，Benjamin R.Buckley et.al.，Tetrahedron Letters 54(2013)843-846；
(3)“Ruthenium-catalyzed directα-alkylation of amides using alcohols”，Boopathy Gnanaprakasam et.al.，Org.Biomol.Chem.，2016，14，9215；
(4)“Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles.Practical Synthesis of N-Unprotected 3，3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring”，
Volk et.al.，Molecules 2017，22，24；
(5)“Transition-Metal-Free C-H Hydroxylation of Carbonyl Compounds”，Boopathy Gnanaprakasam et.al.，Org.Lett.2017，19，3628-3631；
(6)CN103613478A，20140305。
however, in the methods for preparing 3-hydroxy-2-indolone compounds using 3-substituted-2-indolone compounds reported in the prior art as raw materials, the reaction conditions are severe, for example, low temperature of-78 ℃, strong bases such as butyl lithium and potassium tert-butoxide, and/or expensive catalytic systems such as noble metal palladium, ruthenium, phosphorus ligand, etc. are used. Therefore, finding a more efficient, cheaper, greener synthesis remains a challenging topic. In a patent application (application number: CN201710956656.4) previously proposed by the applicant, a novel method for preparing 3-substituted-3-hydroxy-2-indolone compounds is provided, wherein 3-substituted-2-indolone compounds are used as reaction raw materials to react C (sp) at room temperature under the acceleration of TEMPO3) And (3) carrying out an H hydroxylation reaction to obtain a series of target products (formula II) in high yield.
The inventor carries out a series of researches on 3-substituted-3-hydroxy-2-indolone compounds and further provides a novel method for preparing the 3-hydroxy-2-indolone compounds. To the best of the inventor's knowledge, no prior art reports on C (sp) with tert-butyl peroxide (t-BuOOH) as a hydroxyl source3) -H hydroxylation.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method for preparing a 3-hydroxy-2-indolone compound, which has simple process, high efficiency and good atom economy, and takes a 3-substituted-2-indolone compound as a raw material, tert-butyl peroxide (t-BuOOH) and analogues thereof as a hydroxyl source and water as a solvent, so that the 3-hydroxy-2-indolone compound is conveniently prepared and obtained with excellent yield.
The invention provides a preparation method of 3-hydroxy-2-indolone compounds, which takes 3-substituted-2-indolone compounds as raw materials and is prepared by the following steps:
adding the 3-substituted-2-indolone derivative (1a), the compound shown in the formula 2a and solvent water into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted, and carrying out aftertreatment to obtain the target product, namely the 3-hydroxy-2-indolone compound (I).
According to the preparation method of the 3-hydroxy-2-indolone compound provided by the invention, the chemical reaction formula can be expressed as (see formula III);
in the reaction of the third formula, the reaction atmosphere may be an air atmosphere of 1atm, and a nitrogen atmosphere of 1atm or other inert gas atmosphere may be used instead.
The post-processing operation is as follows: and (3) extracting the reaction liquid after the reaction is finished with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain the target product, namely the 3-hydroxy-2-indolone compound (I).
In the 3-substituted-2-indolone compound as the raw material represented by the formula 1a and the 3-hydroxy-2-indolone compound as the product represented by the formula I, R is1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Acyl radical, C1-C6Ester group, halogen, cyano, nitro, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14Heteroaryl, -NRaRb. Wherein R isa，RbIndependently of one another, from C1-C6Alkyl or hydrogen; the heteroatom of the heteroaryl group is selected from O, S or N.
R2Represents hydrogen, C1-C6Alkyl, halogen, cyano, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14A heteroaryl group; the heteroatom of the heteroaryl group is selected from O, S or N.
R3Represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl radical, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14aryl-C1-C6Alkyl radical, C5-C14A heteroaryl group, the heteroatom of which is selected from O, S or N.
Wherein each of the above alkyl, alkoxy, cycloalkyl, aryl and heteroaryl groups may be further substituted with a substituent selected from halogen or C1-C6Alkyl group of (1).
Preferably, R1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl, halogen, C1-C6Alkoxy, nitro, C5-C14An aryl group; wherein said C1-C6Alkyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl group of (1).
Preferably, R2Represents hydrogen, C1-C6Alkyl, halogen, cyano, C5-C14Aryl, wherein said C1-C6Alkyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl group of (1).
Preferably, R3Represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl, phenyl, benzyl, wherein said C1-C6Alkyl and/or C1-C6The acyl, phenyl and/or benzyl groups may be further substituted, the substituents being selected from halogen or C1-C6Alkyl group of (1).
In the compound represented by the above formula 2a, R is4Represents a hydrogen, a tert-butyl group,
(the ". cndot." in the two substituent structural formulae represents the R4The position of attachment of the group to "OOH"). Preferably, R4Represents a tert-butyl group, in which case the compound of formula 2a is tert-butanol peroxide, i.e. t-BuOOH herein.
In the reaction of the present invention, the reaction temperature of the reaction is 40 to 100 ℃, preferably 40 to 80 ℃, and most preferably 60 ℃.
In the reaction of the present invention, Sodium Dodecyl Sulfate (SDS) is preferably added as a surfactant.
In the reaction of the present invention, the molar ratio of the compound of formula 1a to the compound of formula 2a is 1: 1 to 4, preferably, the molar ratio of the compound of formula 1a to the compound of formula 2a is 1: 2 to 3. More preferably, the molar ratio of the compound of formula 1a to the compound of formula 2a is 1: 2. The molar ratio of the compound of formula 1a to SDS is 1: 0.1-0.3, preferably the molar ratio of the compound of formula 1a to SDS is 1: 0.2.
In the reaction of the present invention, water is used as a solvent, and the amount thereof is not particularly limited, and those skilled in the art can select and/or adjust the amount thereof according to the actual conditions of the reaction.
The invention has the beneficial effects that:
1) realization of C (sp) by taking tert-butyl peroxide (t-BuOOH) as hydroxyl source is reported for the first time3) Hydroxylation of the H bond.
2) The tert-butyl peroxide is used as a free radical initiator and a reaction substrate in the reaction, and has higher atom economy.
3) The reaction does not need transition metal catalyst and other additives.
4) The green solvent water is used as a reaction medium, and C (sp) can be realized in the air3) Hydroxylation of the H bond.
5) Simple operation and easy purification.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
EXAMPLE 1 Synthesis of 3-methyl-3-hydroxy-2-indolone, Compound
Adding 3-methyl-2-indolone ((29.4 mg, 0.2 mmol)), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the condition of air atmosphere, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-methyl-3-hydroxy-2-indolone. White solid (83% yield);1H NMR(400MHz，CDCl3)δ：8.18(s，1H)，7.39(d，J＝5.6Hz，1H)，7.26(t，J＝6.0Hz，1H)，7.08(t，J＝6.0Hz，1H)，6.89(d，J＝6.4Hz，1H)，1.61(s，3H)；13C NMR(100MHz，CDCl3)δ：180.6，139.8，131.8，129.6，123.9，123.2，110.4，74.0，24.8。
example 2
The process was carried out in the same manner as in example 1 except that no surfactant SDS was added, whereby the yield of the objective 3-methyl-3-hydroxy-2-indolone was 31% and the recovery rate of 3-methyl-2-indolone was 57%.
Example 3
The charge amount of SDS, the amount of SDS, was reduced to 10 mol% (28.8 mg) of the charge amount of 3-methyl-2-indolone, and the yield of the desired 3-methyl-3-hydroxy-2-indolone was 57% under the same conditions as in example 1.
Example 4
The charge amount of SDS, a surfactant, was increased to 30 mol% (i.e., 28.8mg) of the charge amount of 3-methyl-2-indolone, and the yield of the desired 3-methyl-3-hydroxy-2-indolone was 84% under the same conditions as in example 1.
Example 5
The reaction temperature was 40 ℃ and the other conditions were the same as in example 1, whereby the yield of the objective 3-methyl-3-hydroxy-2-indolone was 41%.
Example 6
The reaction temperature was 80 ℃ and the other conditions were the same as in example 1, whereby the yield of the objective 3-methyl-3-hydroxy-2-indolone was 84%.
Example 7
The charge amount of t-butyl peroxide was 1.2 equivalents (0.24mmol), and the yield of the objective 3-methyl-3-hydroxy-2-indolone was 69% under the same conditions as in example 1.
Example 8
The charge amount of t-butyl peroxide was 3 equivalents (0.6mmol), and the yield of the objective 3-methyl-3-hydroxy-2-indolone was 84% under the same conditions as in example 1.
Example 9
The reaction was carried out under argon, and the other conditions were the same as in example 1, whereby the yield of the objective 3-methyl-3-hydroxy-2-indolone was 83%.
Example 10
Hydrogen peroxide is used to replace the tert-butyl peroxy-alcohol in example 1, the other conditions are the same as in example 1, and the yield of the target product 3-methyl-3-hydroxy-2-indolone is 16%.
Example 11
The tert-butyl peroxide in example 1 was replaced with tert-amyl hydroperoxide, and the yield of the desired 3-methyl-3-hydroxy-2-indolone was 75% as in example 1.
Example 12
The yield of the desired 3-methyl-3-hydroxy-2-indolone was 61% under the same conditions as in example 1 except that α, α -dimethylbenzyl hydroperoxide was used in place of t-butyl peroxide in example 1.
EXAMPLE 13 Synthesis of the Compound 3-Ethyl-3-hydroxy-2-indolinone
Adding 3-ethyl-2-indolone (32.2mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the condition of air atmosphere, monitoring the reaction progress through TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-ethyl-3-hydroxy-2-indolone. White solid (74% yield);1H NMR(400MHz，DMSO-d6)δ：10.20(s，1H)，7.25-7.17(m，2H)，6.96（t，J＝7.6Hz，1H)，6.79(d，J＝7.6Hz，1H)，5.80(s，1H)，1.79-1.73(m，2H)，0.61(t，J＝7.6Hz，3H)；13C NMR(100MHz，DMSO-d6)δ：179.8，142.4，132.3，129.3，124.3，122.0，109.9，76.7，31.1，8.0。
EXAMPLE 14 Synthesis of 3-phenyl-3-hydroxy-2-indolone, Compound
To a Schlenk reaction flask was added 3-phenyl-2-indolone (41.8mg, 0.2mmol), t-butyl peroxide(36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL), placing the reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction progress through TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-phenyl-3-hydroxy-2-indolone. White solid (87% yield);1H NMR(400MHz，DMSO-d6)δ：10.39(s，1H)，7.33-7.22(m，6H)，7.09(d，J＝7.2，1H)，6.96(t，J＝7.6Hz，1H)，6.89(d，J＝7.6Hz，1H)，6.61(s，1H)；13C NMR(100MHz，DMSO-d6)δ：178.9，142.4，142.0，134.2，129.7，128.5，127.9，125.9，125.2，122.5，110.3，77.8。
EXAMPLE 15 Synthesis of the Compound 3- (2, 5-dimethylphenyl) -3-hydroxy-2-indolone
Adding 3- (2, 5-dimethylphenyl) -2-indolone (47.4mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction flask, placing the reaction flask at 60 ℃, stirring and reacting under the condition of air atmosphere, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase by using anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3- (2, 5-dimethylphenyl) -3-hydroxy-2-indolone. White solid (86% yield);1H NMR(400MHz，DMSO-d6)δ：10.51(s，1H)，7.70(s，1H)，7.23(t，J＝7.6Hz，1H)，6.99(d，J＝7.6Hz，1H)，6.92-6.87(m，3H)，6.82(d，J＝7.2Hz，1H)，6.53(s，1H)，2.32(s，3H)，1.72(s，3H)；13C NMR(100MHz，DMSO-d6)δ：177.3，142.1，138.4，133.7，132.0，130.6，130.4，128.9，127.5，126.8，123.9，121，5，109.2，76.1，20.5，17.9。
EXAMPLE 16 Synthesis of 5-methoxy-3-phenyl-3-hydroxy-2-indolone, Compound
Adding a compound 5-methoxy-3-phenyl-2-indolone (47.8mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the air atmosphere condition, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 5-methoxy-3-phenyl-3-hydroxy-2-indolone. White solid (89% yield);1H NMR(400MHz，DMSO-d6)δ：10.28(s，1H)，7.37-7.23(m，6H)，6.84(d，J＝7.2Hz，1H)，6.74(d，J＝8.4Hz，1H)，5.81(s，1H)，3.35(s，3H)；13C NMR(100MHz，DMSO-d6)δ：175.7，153.5，136.1，130.9，129.9，127.7，126.7，125.5，114.2，113.7，110.0，77.2，55.2.。
EXAMPLE 17 Synthesis of the Compound 5-chloro-3-phenyl-3-hydroxy-2-indolone
Adding a compound 5-chloro-3-phenyl-2-indolone (48.6mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the air atmosphere condition, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 5-chloro-3-phenyl-3-hydroxy-2-indolone. White solid (86% yield);1H NMR(400MHz，DMSO-d6)δ：10.55(s，1H)，7.35-7.27(m，6H)，7.10(s，1H)，6.92(d，J＝8.0Hz，1H)，6.79(s，1H)；13C NMR(100MHz，DMSO-d6)δ：178.6，141.3，136.2，129.6，128.8，128.3，128.2，126.5，125.8，125.2，112.0，77.9.。
EXAMPLE 18 Synthesis of 5-bromo-3-phenyl-3-hydroxy-2-indolone, Compound
Adding a compound 5-bromo-3-phenyl-2-indolone (57.4mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction flask, placing the reaction flask at 60 ℃, stirring and reacting under the air atmosphere condition, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 5-bromo-3-phenyl-3-hydroxy-2-indolone. White solid (84% yield):1H NMR(400MHz，DMSO-d6)δ：10.57(s，1H)，7.44(d，J＝8.0Hz，1H)，7.36-7.27(m，5H)，7.21(s，1H)，6.88(d，J＝8.0Hz，1H)，6.78(s，1H)；13C NMR(100MHz，DMSO-d6)δ：178.4，141.7，141.3，136.6，132.5，128.8，128.2，127.9，125.8，114.1，112.5，77.8.。
EXAMPLE 19 Synthesis of 5-nitro-3-phenyl-3-hydroxy-2-indolone, Compound
Adding a compound 5-nitro-3-phenyl-2-indolone (50.8mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the air atmosphere condition, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 5-nitro-3-phenyl-3-hydroxy-2-indolone. White solid (68% yield);1H NMR(400MHz，DMSO-d6)δ：11.16(s，1H)，8.25(d，J＝10.4Hz，1H)，7.90(s，1H)，7.36-7.30(m，5H)，7.13(d，J＝8.8Hz，1H)，7.00(s，1H)；13C NMR(100MHz，DMSO-d6)δ：179.0，149.0，143.0，140.5，135.0，128.9，128.5，127.1，125.8，120.6，110.9，77.4.。
EXAMPLE 20 Synthesis of N-methyl-3-phenyl-3-hydroxy-2-indolone, Compound
Adding a compound N-methyl-3-phenyl-2-indolone (44.6mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the condition of air atmosphere, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography (the elution solvent is ethyl acetate/N-hexane) to obtain the target product N-methyl-3-phenyl-3-hydroxy-2-indolone. White solid (62% yield);1H NMR(400MHz，DMSO-d6)δ：7.37-7.24(m，6H)，7.14(d，J＝7.2Hz，1H)，7.09-7.03(m，2H)，6.68(s，1H)，3.15(s，3H)；13C NMR(100MHz，DMSO-d6)δ：177.2，143.9，141.8，133.5，129.8，128.6，128.0，125.9，124.8，123.2，109.3，77.5，26.6.。
EXAMPLE 21 Synthesis of the Compound N-benzyl-3-phenyl-3-hydroxy-2-indolone
Adding a compound N-methyl-3-phenyl-2-indolone (60mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/N-hexane) to obtain the target product 3-methyl-3-hydroxy-2-indolone. White solid (63% yield);1H NMR(400MHz，DMSO-d6)δ：7.35-7.24(m，11H)，7.17(d，J＝7.2Hz，1H)，7.02(t，J＝7.6Hz，1H)，6.96(d，J＝8.0Hz，1H)，6.84(s，1H)，4.91(s，2H)；13C NMR(100MHz，DMSO-d6)δ：177.3，142.9，141.8，136.8，133.5，129.7，129.1，128.6，128.1，127.9，127.7，125.9，125.0，123.3，109.9，77.5，43.2.。
EXAMPLE 22 Synthesis of the Compound N-phenyl-3-hydroxy-2-indolone
Adding a compound N-phenyl-3-phenyl-2-indolone (57mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃, stirring and reacting under the condition of air atmosphere, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase by using anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and carrying out column chromatography separation on the residue (an elution solvent is ethyl acetate/N-hexane) to obtain the target product 3-methyl-3-hydroxy-2-indolone. White solid (56% yield);1H NMR(400MHz，DMSO-d6)δ：7.60(t，J＝7.6Hz，2H)，7.48(t，J＝8.4Hz，3H)，7.41-7.34(m，4H)，7.30(t，J＝7.6Hz，2H)，7.24(d，J＝7.6Hz，1H)，7.10(t，J＝7.6Hz，1H)，6.92(s，1H)，6.81(d，J＝8.0Hz，1H)；13C NMR(100MHz，DMSO-d6)δ：176.7，143.6，141.7，134.7，133.5，130.2，129.9，128.8，128.6，128.2，127.1，125.9，125.4，123.9，109.7，77.5.。
EXAMPLE 23 Synthesis of the Compound 5-bromo-3- (2, 5-dimethylphenyl) -3-hydroxy-2-indolone
Adding a compound 5-bromo-3- (2, 5-dimethylphenyl) -2-indolone (63mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction flask, placing the reaction flask at 60 ℃ under the condition of air atmosphere for stirring reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase by using anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-methyl-3-hydroxy-2-indolone. White solid (81% yield);1H NMR(400MHz，DMSO-d6)δ：10.69(s，1H)，7.69(s，1H)，7.43(d，J＝8.0Hz，1H)，7.03(d，J＝7.6Hz，1H)，6.94(d，J＝8.0Hz，1H)，6.91(s，1H)，6.87，(d，J＝8.4Hz，1H)，6.75，(s，1H)，2.33(s，3H)，1.74(s，3H)；13C NMR(100MHz，DMSO-d6)δ：177.7，142.3，138.6，135.2，134.8，132.5，131.4(2)，128.7，127.7，127.4，114.0，112.3，76.9，21.4，18.8.。
EXAMPLE 24 Synthesis of the Compound 5-chloro-3-ethyl-3-hydroxy-2-indolone
Adding a compound 5-chloro-3-ethyl-2-indolone (39mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted (the reaction time is 24 hours), extracting the reaction liquid after the reaction is completed with ethyl acetate for three times, drying an organic phase by using anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and carrying out column chromatography separation on the residue (an elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-methyl-3-hydroxy-2-indolone. White solid (72% yield);1H NMR(400MHz，DMSO-d6)δ：10.35(s，1H)，7.26(d，J＝11.2Hz，2H)，6.81(d，J＝8.4Hz，1H)，5.97(s，1H)，1.81-1.76(m，2H)，0.61(t，J＝7.6Hz，3H)；13C NMR(100MHz，DMSO-d6)δ：179.4，141.2，134.4，129.1，126.1，124.4，111.4，76.9，30.9，7.9.。
EXAMPLE 25 Synthesis of the Compound N-methyl-5-chloro-3-phenyl-3-hydroxy-2-indolone
Adding the compound N-methyl-5-chloro-3-phenyl-2-indolone (51.4mg, 0.2mmol), tert-butyl peroxide (36mg, 0.4mmol), SDS (sodium dodecyl sulfate, 57.6mg, 0.04mmol) and solvent water (2mL) into a Schlenk reaction flask, placing the reaction flask at 60 ℃, stirring and reacting under the condition of air atmosphere, monitoring the reaction progress by TLC or GC until the raw materials react completely (reaction time is 24 hours), extracting the reaction solution after the reaction is completed with ethyl acetate three times, drying the organic phase with anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove the solutionAnd (3) separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-methyl-3-hydroxy-2-indolone. White solid (60% yield):1H NMR(400MHz，DMSO-d6)δ：7.43(d，J＝8.4Hz，1H)，7.35-7.27(m，5H)，7.16-7.12(m，2H)，6.84(s，1H)，3.16(s，3H)；13C NMR(100MHz，DMSO-d6)δ：176.8，142.8，141.1，135.4，129.6，128.7，128.3，127.2，125.9，124.8，111.0，77.5，26.8.。
example 26 reaction mechanism control test
(1) The procedure of example 14 was followed except that di-tert-butyl peroxide was used in place of tert-butyl peroxide in example 14. The reaction was not obtained by GC detection
And the starting 3-phenyl-2-indolinone is recovered in greater than 90% recovery.
(2) By H2 18O replaces the solvent water in the example 14, the HRMS analysis determines that the hydroxyl oxygen atom in the target product 3-phenyl-3-hydroxy-2-indolone is still16O, it is understood that in the reaction of the present invention, the hydroxyl group is derived from t-butanol peroxide.
(3) When 2.4 equivalents of BHT (2, 6-di-tert-butyl) -4-methylphenol or hydroquinone were added as a radical scavenger to the reaction of example 14, the yield of the target product of the reaction was significantly reduced to 28% and 21%, respectively.
It follows that the possible reaction mechanism of the present invention can be deduced as shown in the following formula:
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (5)
1. A preparation method of 3-substituted-3-hydroxy-2-indolone compounds is characterized by comprising the following steps: adding a 3-substituted-2-indolone derivative shown in a formula 1a, a compound shown in a formula 2a and solvent water into a Schlenk reaction bottle, placing the reaction bottle under the conditions of a certain temperature and air atmosphere, stirring for reaction, and carrying out post-treatment after the reaction is completed to obtain a target product, namely a 3-substituted-3-hydroxy-2-indolone compound I; the reaction formula is shown as follows:
in the compounds of formula 1a and formula I, R1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Acyl radical, C1-C6Ester group, halogen, cyano, nitro, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14Heteroaryl, -NRaRb(ii) a Wherein R isa，RbIndependently of one another, from C1-C6Alkyl or hydrogen;
R2represents hydrogen, C1-C6Alkyl, halogen, cyano, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14A heteroaryl group;
R3represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl radical, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14aryl-C1-C6Alkyl radical, C5-C14A heteroaryl group;
wherein the heteroatom of the heteroaryl group is selected from O, S or N;
and the above-mentioned alkyl and alkoxy groupsCycloalkyl, aryl and heteroaryl groups may be further substituted with a substituent selected from halogen or C1-C6Alkyl groups of (a);
in the compound represented by the formula 2a, R4Represents a tert-butyl group,
Wherein, Sodium Dodecyl Sulfate (SDS) is added as a surfactant in the preparation method;
the certain temperature is 40-100 ℃;
the molar ratio of the compound of the formula 1a to the compound of the formula 2a is 1: 1-4; the molar ratio of the compound of formula 1a to SDS is 1: 0.1-0.3.
2. The method of claim 1, wherein R is1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl, halogen, C1-C6Alkoxy, nitro, C5-C14An aryl group; wherein said C1-C6Alkyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl groups of (a);
R2represents hydrogen, C1-C6Alkyl, halogen, cyano, C5-C14Aryl, wherein said C1-C6Alkyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl groups of (a);
R3represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl, phenyl, benzyl, wherein said C1-C6The alkyl, phenyl and/or benzyl groups may be further substituted, the substituents being selected from halogen or C1-C6Alkyl groups of (a);
R4is a tert-butyl group.
3. The method of claim 1, wherein the defined temperature is 60 ℃.
4. The method of claim 1, wherein the molar ratio of the compound of formula 1a to the compound of formula 2a is 1: 2; the molar ratio of the compound of formula 1a to SDS was 1: 0.2.
5. A method according to any of claims 1-2, characterized in that the post-processing operation is as follows: extracting the reaction solution after the reaction is finished with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 3-substituted-3-hydroxy-2-indolone compound I.
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